PROJECT SUMMARY Neurocognitive deficits represent a core component of several major neuropsychiatric disorders, including schizophrenia, affective disorders, autism spectrum disorders, and attention-deficit/hyperactivity disorder (ADHD), and the centrality of cognition to mental health is reflected in the RDoC matrix, in which ?Cognitive Systems? is one of the five fundamental domains of investigation. However, the genetic column of the RDoC matrix is currently empty, as it has been recognized that the earlier generation of candidate gene approaches lacked sufficient power and replicability. The Cognitive Genomics Consortium (COGENT), led by the PI of this application, was formed earlier this decade to perform large scale genome-wide association studies (GWAS) of cognitive phenotypes. Most recently, we have meta-analyzed our results with other large-scale cohorts, resulting in two studies with >100,000 subjects in each, which have finally identified dozens of genome-wide significant loci for general cognitive ability (GCA). We have also demonstrated the significant genetic overlap, at the level of genome- wide polygene scores, between general cognitive ability and most forms of psychiatric illness. Deconstructing the genetic overlap between cognition and risk for neuropsychiatric illness can provide useful etiological insights and help identify novel druggable targets. In the proposed study, we aim to extend our cognitive GWAS to specific cognitive domains (e.g., verbal memory, working memory, attention, and processing speed) with sample sizes in the tens of thousands for each. We will then utilize our general and specific cognitive GWAS results to identify key molecular mechanisms and pathways that can identify nootropic drug targets (Aim 1). We will then examine the molecular genetic overlap between our cognitive GWAS results and psychiatric illness, utilizing novel analytic approaches to tease apart dissociable mechanisms (Aim 2). Finally, we will utilize publicly available neuroimaging datasets with concomitant GWAS data to examine the circuit-based, neurodevelopmental manifestations of cognition-relevant alleles and polygene scores (Aim 3).